Many compounds can exist in different crystal forms, or polymorphs. Individual polymorphs can exhibit different physical, chemical, and spectroscopic properties. For example, certain polymorphs may be more readily soluble in particular solvents, may flow more readily, or may compress more easily than others. See, e.g., P. DiMartino, et al., J. Thermal Anal., 48:447–458 (1997). In the case of drugs, certain forms may be more bioavailable than others, while others may be more stable under certain manufacturing, storage, and biological conditions. This is particularly important from a regulatory standpoint, since drugs are approved by agencies such as the United States Food and Drug Administration (“FDA”) only if they meet exacting purity and characterization standards. Indeed, the regulatory approval of one polymorph of a compound, which exhibits certain solubility and physico-chemical (including spectroscopic) properties, typically does not imply the ready approval of other polymorphs of that same compound.
One compound, which has received a lot of attention in connection with polymorphism, is Ritonavir. Ritonavir is chemically named 10-hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,11R*)], and has the following structural formula:

Ritonavir is an inhibitor of the HIV-1 and HIV-2 proteases with in vitro and in vivo activity against the Human Immunodeficiency Virus (“HIV”), and is presently sold in a soft gelatin capsule dosage form for oral administration under the trade name NORVIR® (Abbott Laboratories, North Chicago, Ill. USA). NORVIR® is indicated for use in combination with other antiretroviral agents for the treatment of HIV-infection. PHYSICIANS' DESK REFERENCE, 487–492 (56th ed., 2002). The combination of Ritonavir and Lopinavir is sold in a capsule dosage form for oral administration under the trade name KALETRA™, which is also indicated for use in combination with other antiretroviral agents for the treatment of HIV-infection. Id. at 471–478.
During the development and initial manufacture of Ritonavir, only one crystal form was identified. Bauer, J., et al., Pharm. Res., 18(6):859–866 (2001). Because Ritonavir is not bioavailable in that form, however, the initially marketed oral formulations that comprised it contained Ritonavir dissolved in a semi-solid, waxy matrix filled into capsules. About two years after the initial marketing of NORVIR®, a second crystal form of Ritonavir was discovered; its presence in the capsule formulation caused the product to fail the dissolution specification mandated by the regulatory agencies. Id. As it later turned out, this new form, which is referred to as “Form II,” was supersaturated in the hydroalcoholic solutions used in the drug formulations, even though the originally known form, which is now referred to as “Form I,” was not. The sudden appearance of the significantly less soluble Form II prevented the further manufacture of the original NORVIR® formulations, and seriously threatened the supply of the drug. Id. At some considerable cost, a new formulation of NORVIR® was eventually developed.
Until now, only two crystalline forms of Ritonavir—Forms I and II—were known. Id.; Chemburkar, S. R., et al., Organic Process Res. Dev., 4:413–417 (2000) (“Chemburkar”). Form I has a melting point of 122° C.; Form II has a melting point of 125° C. Chemburkar et al.
A need exists for other crystalline forms of Ritonavir, and bioavailable crystalline forms in particular. A need also exists for crystalline forms of the drug that can be used to more readily manufacture Forms I and II. Forms of Ritonavir are also desired which, when combined with other drugs, can be used to provide combination therapies that are more effective and/or better tolerated than those currently in use.
HIV infection is often treated using combination therapies, wherein two or more pharmaceutically active compounds are administered to the patient (e.g., together as a “drug cocktail”). Current therapies for HIV infection focus on inhibiting the activity of viral enzymes that are critical in the life cycle of the virus, such as reverse transcriptase and protease. Antiretrovirals that are presently in use are generally grouped into three classes: nucleoside reverse transcriptase inhibitors (“NRTIs”); non-nucleoside reverse transcriptase inhibitors (“NNRTIs”); and protease inhibitors (“PIs”). Combination therapies using such compounds have been shown to reduce the incidence of opportunistic infections and to increase survival time. It is possible that these and other benefits of combination therapies may be further improved by the use of new crystalline forms of Ritonavir.